Project Summary/Abstract Transcranial direct current stimulation (tDCS) is a safe, well-tolerated and low-cost treatment approach and has shown effective therapeutic effects in managing symptoms and to enhancing recovery in patients with multiple sclerosis (MS). Despite positive clinical findings, the underlying mechanism of tDCS remains largely unclear. There is a current gap of knowledge of how and whether externally-applied tDCS modifies neural activity and oxygen metabolism in MS, as well as how and whether alleviated symptoms of MS due to tDCS correlate with neuronal metabolic changes. The proposed project will use advanced MRI techniques to test immediate (by simultaneous MRI), cumulative (at the end of 30 tDCS treatment sessions), and lingering (3 months after treatment) effects of tDCS on neuronal metabolism (e.g., cerebral metabolic rate of oxygen or CMRO2) in patients with secondary progressive MS (SPMS). Further, tDCS can be used as a challenge known to increase neural activity measured with CMRO2 using MRI as a physiological maneuver to examine the brain reserves or plasticity, through which we will develop biomarker of neuronal reactivity (NR) (i.e., percent increase of CMRO2) induced by the current stimulation. Additionally, we will correlate the tDCS modulation of brain network connectivity measured with resting state functional MRI and clinical improvement. The specific aims of the project are 1) To compare CMRO2 levels during sham, simultaneous tDCS and immediately after stimulation on baseline MR and at the end of 30 home-based tDCS sessions in patients with SPMS; 2) To determine the brain network connectivity changes between baseline and after 30 sessions home-based tDCS modulation; 3) To assess the relationship between the baseline NR (i.e., percent increase of CMRO2), ?NR (change from baseline to 30 home-based sessions), connectivity measures, and behavioral outcome measures (fatigue and neurocognitive function) assessed at each MRI visit and 3 months after tDCS treatment. Such information is critical in providing objective and direct neuronal biophysiological evidence of tDCS modulation, with a strong potential to guide and interpret how tDCS interventions can slow down or prevent disease progression in these patients.